Obesity is a widely prevalent body weight disorder, affecting an estimated 30 to 50% of the middle-aged population in the western world. Obesity, defined as a body mass index (BMI) of 30 or more, contributes to diseases such as coronary artery disease, hypertension, stroke, diabetes, hyperlipidemia and some cancers. It is a complex multifactorial chronic disease that develops from an interaction of genotype and the environment and involves social, behavioral, cultural, physiological, metabolic and genetic factors.
Adipose tissue consists primarily of adipocytes. Vertebrates possess two distinct types of adipose tissue: white adipose tissue (WAT) and brown adipose tissue (BAT), which has a phenotype in adult humans commonly referred to as “beige” fat. WAT stores and releases fat according to the nutritional needs of the animal. This stored fat is used by the body for heat insulation, mechanical cushioning, and as a source of energy. BAT burns fat, releasing the energy as heat through thermogenesis. BAT thermogenesis is used both to maintain homeothermy by increasing thermogenesis in response to lower temperatures and to maintain energy balance by increasing energy expenditure in response to increases in caloric intake. In humans, and to a lesser extent rodents, brown fat diminishes with age, but can be re-activated under certain conditions.
In the development of obesity, an increase in adipose tissue mass can be due to an increase in both the size (hypertrophic growth) and number (hyperplastic growth) of adipocytes. Hypertrophic growth is an increase in size of adipocytes stimulated by lipid accumulation. Hyperplastic growth is defined as an increase in the number of adipocytes in adipose tissue, for example as result of recruitment of preadipocytes from a population of multipotent stem cells or from sub-populations of cells resident in mature white adipose tissue (WAT). It is thought to occur primarily by mitosis of pre-existing adipocytes caused when adipocytes fill with lipid and reach a critical size. An increase in the number of adipocytes has far-reaching consequences for the treatment and prevention of obesity.
Current therapies for obesity predominantly lead to decreased energy intake by acting at satiety centers in the brain or by reducing the efficiency of intestinal absorption. To date, no safe and reliable molecular mechanism has been found for treating and/or preventing obesity by altering the composition of adipose tissues to generate more brown fat cells. Given the severity and prevalence of obesity related disorders, there exists a great need for the identification of an anti-obesity therapeutic.